RU2769988C1 - Combined hypnotic agent in the form of tablets - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to the field of pharmaceuticals, namely, to medicinal products in the form of tablets used as a hypnotic agent. The combined hypnotic agent in the form of tablets contains melatonin, peppermint leaf oil, motherwort herb extract, and excipients. The components are used in the claimed quantities.

EFFECT: use of the invention normalises the effect of melatonin on the circadian sleep rhythm, improves the quality of sleep and enhances the adaptogenic properties.

3 cl, 10 ex

Description

The invention relates to pharmaceutics, namely to medicines in the form of tablets used as an adaptogenic, hypnotic and sedative.

The results of studies of the manifestations of insomnia conducted in the world show a constant increase in the number of people suffering from sleep disorders. Among the various options for sleep disorders, insomnia (insomnia) is the leader, the prevalence of which is estimated at 9-15% (Lichstein KL, Taylor DJ, McCrae CS, Petrov ME. Insomnia: epidemiology and risk factors. Principles and Practice of Sleep Medicine. 6 ^th ed Philadelphia: Elsevier, 2016: 761-768). According to the International Classification of Sleep Disorders, insomnia is defined as a syndrome characterized by the presence of recurring disturbances in the initiation, duration, consolidation, or quality of sleep that occurs despite sufficient conditions and amount of time for sleep, and is manifested by various disturbances in daytime activities (American Academy of Sleep Medicine. International classification of sleep disorders, 3 ed.: Diagnostic and coding manual Westchester, 111.: American Academy of Sleep Medicine, 2014.

The range of drugs used for sleep disorders is very extensive, and not all of them are typical hypnotics, but are often representatives of various classes of psychotropic drugs. Modern sleeping pills, subject to the necessary rules, allow you to get the necessary hypnotic effect, not accompanied by negative changes in the structure of sleep and the quality of subsequent wakefulness. Currently, drugs from the following pharmacological groups are used: non-benzodiazepine benzodiazepine receptor agonists (Zopiclone, Zolpidem, Zaleplon); benzodiazepine benzodiazepine receptor agonists (Phenazepam, Oxazepam, Lorazepam, Diazepam, Nitrazepam, Clonazepam); melatonin preparations and melatonin receptor agonists (Melatonin, Ramelteon); Hi-histamine receptor blockers (Doxylamine, Diphenhydramine); antidepressants (Trazodone, Mianserin, Agomelatine, Amitriptyline, Trimipramine, Doxepin, Mirtazapine); antipsychotics (Quetiapine, Chlorprothixen, Protipendil, Levomepromazine, Melperone, Pipamperon, Olanzapine); anticonvulsants (Gabapentin); sedatives (Preparations of valerian, hops, lemon balm, passionflower) (S.V. Okovity, I.A. Titovich. "Pharmacological principles of the treatment of insomnia". Medical Council. No. 6, 2018, pp. 26-32).

However, the listed drugs, with the exception of melatonin preparations and sedatives based on herbal ingredients, are characterized by numerous contraindications and side effects, and a number of drugs, in particular Phenazepam, are addictive and lose their effect when taken systematically. Monocomponent preparations of melatonin and sedative preparations based on herbal raw materials are generally not effective enough and do not always produce the desired effect. Thus, the use of melatonin preparations as a hypnotic agent requires compliance with sleep hygiene. Sleep with the lights on, light noise (especially the blue spectrum) contributes to the destruction of melatonin and reduce its effectiveness. A number of studies have shown that when taking melatonin for a long time, its effectiveness increased after six months of therapy, compared with the results in the first month of treatment (Yu.V. Bykov, A.N. Khannanova, R.A. Becker. "Melatonin and benzodiazepines in the treatment of insomnia: pros and cons (literature review)" In the world of scientific discoveries, No. 7(79), 2016, pp. 60-82).

At the same time, it should be taken into account that therapy with melatonin preparations is predominantly successful when it is combined with traditional medicines. Performing a modulatory function in the body, melatonin often acts as a contributing therapeutic factor, while being able to limit unwanted side reactions of other substances (E.B. Arushanyan. "Universal therapeutic possibilities of melatonin." Clinical Medicine. No. 2, 2013, p. 4- eight). At the same time, the interaction of melatonin with other drugs has been little studied, while the high reactivity of melatonin, its high antioxidant activity and the ability to take part in the vast majority of biochemical processes in the body are widely known (D.V. Vasendin. “Medical and biological effects melatonin: some results and perspectives of the study". Bulletin of the Russian Military Medical Academy. No. 3 (55), 2016, pp. 171-178. A. Yu. Bespyatykh, V. Ya. Brodsky, O. V. Burlakova, V. A. Golichenkov, L. A. Voznesenskaya, D. B. Kolesnikov, A. Yu. Molchanov, S. I. Rapoport Melatonin: theory and practice, edited by S. I. Rapoport, V. A. Golichenkov. M., 2009).

The objective of the present invention is the creation of an effective drug for combating insomnia.

The technical result is to enhance the normalizing effect of melatonin on the circadian rhythm of sleep, improve the quality of sleep and provide an adaptogenic effect.

The problem is solved, and the technical result is achieved by the fact that the combined hypnotic in the form of tablets contains melatonin, peppermint leaf oil, motherwort herb extract and excipients in the following amount to the weight of the tablet, wt. %:

Peppermint leaf oil 0.17-2.55 motherwort herb extract (in terms of dry matter) 3.92-26.73 Melatonin 0.75-42.38 Excipients rest.

Excipients include cyclodextrin at a ratio of the content of cyclodextrin to the amount of peppermint leaves oil and motherwort herb extract by weight in the range of 1:0.06-1.8. In a particular case, it contains betadex as a cyclodextrin.

The excipients of the tablet contain lactose monohydrate, cyclodextrin, starch, microcrystalline cellulose, medium molecular weight polyvinylpyrrolidone, talc and calcium stearate.

The tablet may be coated with one or more coatings of conventional composition, for example Opadry II 85F18422 White film coating, manufactured by Colorcon, UK, may be used. This shell contains polyvinyl alcohol (partially hydrolyzed), titanium dioxide, macrogol and talc. Also, the tablet can be film-coated with Opadry II Blue 13A205000 manufactured by the same company and containing hypromellose, talc, povidone, titanium dioxide, polysorbate 80, indigo carmine, brilliant blue, iron oxide yellow.

The tablet may be coated with one of these coatings or both - one on top of the other.

This composition of the tablet was obtained after numerous experiments on the selection and study of the interaction of ingredients, their effect on the human body. When using the claimed composition and structure of the tablet, an increase in the total score of the questionnaire was noted for scoring the subjective characteristics of sleep in patients with insomnia caused by dyssynchronosis compared with a melatonin monopreparation, for example, such as the well-known drug Melaxen. The claimed combined agent is prepared as follows.

Example 1

The process of obtaining a combined agent is carried out in three stages, at the first of which a mixture is prepared from an alcohol solution with peppermint oil. Separately, betadex (β-cyclodextrin), melatonin and purified water are mixed. The resulting mixtures are combined, stirred, granulated and dried. At the second stage, a solution of medium molecular weight povidone and a mixture of potato starch with microcrystalline cellulose PH 101, lactose monohydrate are prepared. The resulting mixture is moistened with a solution of povidone. After moistening, the mass is granulated and dried. At the third stage, the obtained granulates are combined and sequentially mixed with motherwort herb extract, talc and calcium stearate. As a result, a tableting mass is obtained, which is subjected to compression on a tablet press to obtain a finished tablet. The tablet has a round biconvex shape from light brown to dark brown with patches of dark and white. The tablet may optionally be coated with one or more film coats. The finished product with a shell is a round biconvex film-coated tablets from light blue to blue. On a transverse section, the core is light brown in color with patches of a darker and lighter color.

To prepare a tablet, the ingredients are taken in the following amount in wt. %:

Melatonin 23.08 Peppermint leaf oil 0.79 motherwort herb extract (in terms of dry matter) 19.05 Excipients the rest up to 100

The ratio of the content of cyclodextrin (betadex) to the amount of peppermint leaf oil and motherwort herb extract by weight for this example is 1:0.7.

Example 2

The combined agent is prepared as in example 1, but for the preparation of a tablet, the ingredients are taken in the following amount in mass. %:

Melatonin 42.38 Peppermint leaf oil 0.17 motherwort herb extract (in terms of dry matter) 3.92 Excipients the rest up to 100

The ratio of the content of cyclodextrin (betadex) to the amount of peppermint leaves oil and motherwort herb extract by weight for this example is 1:0.06 The finished product is a round biconvex tablets of light brown color.

Example 3

The combined agent is prepared as in example 1, but 2-hydroxypropyl-γ-cyclodextrin is used as a cyclodextrin to prepare a tablet, and the ingredients are taken in the following amount in wt%:

Melatonin 0.75 Peppermint leaf oil 2.55 motherwort herb extract (in terms of dry matter) 26.73 Excipients the rest up to 100

The ratio of cyclodextrin content (2-hydroxypropyl-γ-cyclodextrin) to the sum of peppermint leaf oil and motherwort herb extract by weight for this example is 1:1.8

The finished product is a round, biconvex, light blue film-coated tablet.

Example 4

The combined agent is prepared as in example 1, but methyl-β-cyclodextrin is used as a cyclodextrin to prepare a tablet, and the ingredients are taken in the following amount in wt%:

Melatonin 5.7 Peppermint leaf oil 0.85 motherwort herb extract (in terms of dry matter) 16.55 Excipients the rest up to 100

The ratio of cyclodextrin content (Methyl-β-cyclodextrin) to the sum of peppermint leaf oil and motherwort herb extract by weight for this example is 1:0.424

The finished product is a round, biconvex, light blue film-coated tablet.

Example 5

The combination agent is prepared as in example 1, but, for the preparation of a tablet, α-cyclodextrin is used as cyclodextrin, and the ingredients are taken in the following amount in mg per g:

Melatonin 15.5 Peppermint leaf oil 1.38 motherwort herb extract (in terms of dry matter) 19.5 Excipients the rest up to 100

The ratio of the content of cyclodextrin (α-cyclodextrin) to the amount of peppermint leaf oil and motherwort herb extract by weight for this example is 1:0.55

The finished product is a round, biconvex, dark brown tablet.

Example 6

The combination agent is prepared as in example 1, but, for the preparation of a tablet, α-cyclodextrin is used as cyclodextrin, and the ingredients are taken in the following amount in mg per g:

Melatonin 35.0 Peppermint leaf oil 0.38 motherwort herb extract (in terms of dry matter) 9.5 Excipients the rest up to 100

The ratio of the content of cyclodextrin α-cyclodextrin) to the amount of peppermint leaf oil and motherwort herb extract by weight for this example is 1:0.55

The finished product is a round, biconvex, blue film-coated tablet.

Example 7

The combined agent is prepared as in example 1, but for the preparation of a tablet, the ingredients are taken in the following amount in mass. %:

Melatonin 2.78 Peppermint leaf oil 0.17 motherwort herb extract (in terms of dry matter) 3.92 Excipients the rest up to 100

The ratio of the content of cyclodextrin (betadex) to the amount of peppermint leaves oil and motherwort herb extract by weight for this example is 1:1.8

The finished product is a light brown round biconvex tablet.

Example 8

The combined agent is prepared as in example 1, but for the preparation of a tablet, the ingredients are taken in the following amount in mass. %:

Melatonin 12.8 Peppermint leaf oil 2.17 motherwort herb extract (in terms of dry matter) 13.12 Excipients the rest up to 100

The ratio of the content of cyclodextrin (betadex) to the amount of peppermint leaf oil and motherwort herb extract by weight for this example is 1:0.6

The finished product is a round, biconvex brown tablet.

The following examples demonstrate the therapeutic efficacy of the claimed drug.

Example 9

At the preclinical stage, a comparative study of the effectiveness of the claimed combined preparation according to example 1 was carried out on mice in which the state of insomnia caused by dyssynchronosis was modeled by mechanical sleep deprivation. As a result, in mice, disorders characteristic of insomnia caused by dyssynchronosis were noted in the form of adaptation disorders, expressed in a decrease in physical performance and an increase in anxiety.

Using the rotating rod technique ("rotard"), it was shown that intragastric administration of the claimed drug (n=10) and melatonin (n=10) in an amount equivalent to one therapeutic dose leads to a comparable increase in physical performance - an increase in the reduced period of falling - up to 115.7±4.3 s. and 115.2±3.8 s. respectively. In both cases, the difference with placebo (n=10), where the value of the indicator was 71.8±14.0 s, was statistically significant (p<0.05).

The use of the "light-dark chamber" test demonstrated the advantage of the claimed drug over melatonin in terms of its effect on the body's adaptive capabilities disturbed by insomnia, manifested by an increase in anxiety. Thus, the latent period of the first transition into the dark chamber against the background of intragastric administration of the claimed preparation according to the invention was significantly higher than against the background of intragastric administration of melatonin in doses equivalent to one therapeutic dose - 43.56 ± 8.20 s. versus 21.0±2.8 s. (p<0.05). Statistically significant differences were also recorded regarding the effect on the number of transitions between compartments of 30.5±2.7 versus 23.2±3.5 s. (p<0.05).

Example 10

A clinical trial randomized 140 patients aged 18 to 55 years with insomnia of non-organic etiology due to dyssynchronosis. Of these, 70 (main group) received the combined agent according to the invention at a dose of 1 tablet (163 mg total weight, of which 3 mg is melatonin) 30-40 minutes before bedtime for 28 days. 70 patients (control group) received melatonin - 1 tablet of Melaxen (3 mg of melatonin) 30-40 minutes before bedtime for 28 days. In the main group, 69 patients completed treatment, in the control group - 70 patients. The comparative effectiveness of therapy was determined by the change in the total score of the subjective characteristics scoring questionnaire, which included 6 parameters - the time to fall asleep, the duration of sleep, the number of night awakenings, the quality of sleep, the number of dreams, the quality of awakening. Before the start of treatment, the values of the total score in the main and control groups were comparable - 14.9±1.9 and 15.7±2.1. During therapy, there was a statistically significant increase in the total total score in both groups to 25.2±3.9 and 22.0±3.0 (p<0.05). At the same time, in the main group that received the drug according to this invention, the severity of the normalizing effect on the biological rhythms of sleep turned out to be significantly more significant, as evidenced by the statistical significance of the differences in the values of the indicator after completion of treatment, as well as its significantly more pronounced dynamics in points - 10.2± 4.2 and 6.1±3.8 (p<0.05).

Thus, the results obtained indicate that the claimed complex preparation contributes to the organization of the biological rhythm and the normalization of night sleep, and also has an adaptogenic effect in case of dyssynchronosis. At the same time, it surpasses melatonin in the severity of these effects. Previously, for the active components of mint and motherwort, no effect on the biological rhythms of sleep, as well as an adaptogenic effect, was described. At the same time, the presence of certain chronobiotic effects in them suggests the possibility of synergism with melatonin and enhancement of its main pharmacodynamic effects.

Claims (4)

1. A combined hypnotic in the form of tablets containing melatonin, peppermint leaf oil, motherwort herb extract and excipients in the following amount to the weight of the tablet, wt.%: Peppermint leaf oil 0.17-2.55 motherwort herb extract (in terms of dry matter) 3.92-26.73 Melatonin 0.75-42.38 Excipients rest 2. A combined agent according to claim 1, characterized in that the excipients include cyclodextrin at a ratio of cyclodextrin content to the sum of peppermint leaves oil and motherwort herb extract by weight within the range of 1:0.06-1.8. 3. The combined agent according to claim 2, characterized in that it contains betadex as a cyclodextrin.